Opioid polymer release system

ABSTRACT

A pharmaceutical composition for controlled release of an active substance is provided. The active substance is released into an aqueous medium by erosion of at least one surface of the composition. The composition comprises i) a matrix comprising a) polymer or a mixture of polymers, b) an active substance and, optionally, c) one or more pharmaceutically acceptable excipients, and ii) a coating.

FIELD OF THE INVENTION

The present invention relates to a novel pharmaceutical composition forcontrolled release of an opioid like e.g. morphine into an aqueousmedium. The pharmaceutical composition is a coated matrix composition inwhich the matrix composition comprises a) a polymer or a mixture ofpolymers, b) an opioid like e.g. morphine and, optionally, c) one ormore pharmaceutically acceptable exciplents. The coating remains intactduring the release phase and may thereafter crumble and/or erode.Furthermore, the coating covers the matrix composition in such a mannerthat only a specific surface area of the matrix composition is subjectto erosion in an aqueous medium. i.e. the surface area from which theactive substance is release is kept substantial constant during the timeperiod.

The polymer mentioned under a) above may suitably be a substantiallywater soluble or crystalline polymer or a mixture of substantially watersoluble and/or crystalline polymers

The design of the pharmaceutical composition is based on the findingthat it is possible to control the release from such a composition byensuring that the release predominantly takes place by erosion. In orderto ensure erosion based release a balance must be obtained between thediffusion rate of water into the matrix composition and the dissolutionrate of the matrix composition.

Accordingly, the invention relates to an opioid containingpharmaceutical composition for oral use, which provides zero orderrelease based on controlling the balance between matrix erosion rate anddiffusion rate in the matrix.

The invention also provides various combinations of immediate releaseopioid compositions and controlled release opioid compositions.

DISCLOSURE OF THE INVENTION

The present invention relates to a controlled release compositioncomprising an opioid as a therapeutically, prophylactically and/ordiagnostically active substance. The opioids are generally used inanalgesic treatment and there is a need for developing compositions fororal use, which have a lower administration frequency. Thus once ortwice daily administrations would be preferred. A controlled releasecomposition according to the invention aim at a zero order release ofthe opioid in a predetermined pattern to reduce and/or delay the peakplasma concentration without affecting the extent of drugbioavailability. The frequency of undesirable side effects may bereduced and due to the delay in the time it may take to obtain the peakplasma concentration and the extension of the time at thetherapeutically active plasma concentration, the frequency of theadministration may be reduced to a dosage taken only twice or oncedaily. This also serves to improve patient compliance. A furtheradvantage of the controlled release composition is that high localconcentrations of the opioid in the gastrointestinal tract are avoideddue to the erosion-based release mechanism.

Patients suffering from chronic pains very often require a high dailydosage of an analgesic. If such a high dosage of an opioid should begiven only once or twice daily, the release from the composition must besafe. The composition should also be storage stable with respect tochemical and physical stability.

Morphine is probably one of the most commonly used analgesics in thecontrol of severe pain. Due to the short half-life of morphine ofapproximately 2 hours, the analgesic must be administered frequently,e.g. every 3-4 hours to maintain a patient pain free. This regime mayrequire a 2 a.m. dose to prevent early morning recurrence of pain.

To obtain therapeutic plasma concentrations with less frequent dosing,effective controlled release analgesics are under continuousdevelopment. An ideal controlled release analgesic should exhibit thefollowing properties: prevent pain ‘break-through’, eliminate majorplasma concentration fluctuations, produce prolongation of effectivedrug levels, produce effective analgesia without unwanted side effectssuch as sedation.

In other words, in addition to a less frequent administration, the realchallenge in controlled release delivery may be expressed by the goal ofdecreasing the incidence of adverse effects and at the same timeincreasing the effect of the treatment. This can only be obtained by aninteraction between the specific pharmacological properties of theactive ingredient and the composition.

Many controlled release products on the market suffers from the lack ofa true controlled release. In fact, Dolcontin, which covers most of themarket for sustained morphine, results in a plasma profile rathersimilar with an immediate release dosage formulation only with a slightdecrease in the initial burst. During the repeated administration, theplasma concentration with this product will necessarily exhibit theundesired peaks and troughs. This may be avoided with the opioidcomposition according to the present invention.

Controlled release is not only the effect of prolonging the release ofactive ingredient from the composition by increasing the dosage anddecreasing the initial burst. The optimised effect is only obtained whenthe right balance is obtained between the maximum concentration, theduration of the time where the plasma concentration is above the minimumtherapeutic level and the administered dosage.

High concentrations or a fast rise in the concentration of morphine isone important factor resulting in side effects including the risk ofgetting addicted to morphine. The fear of addiction is often a majorobstacle for initiation of the otherwise effective pain treatment withmorphine both in the view of the clinical personnel as well as in theview of the patients themselves.

High concentrations during longer periods induce resistance on receptorlevel and should also be avoided. By “high” is here meant any plasmaconcentration above the pain relieving level. Other important sideeffects of morphine are the respiratory depressing effect and sedation;both are highly correlated to the plasma concentration. In addition,memory and motor control, important aspects in relation with long termtreatment, may already be present within the therapeutic level andaccordingly, any unnecessary high concentration of morphine should beavoided.

According to the present invention it is possible to obtain acomposition, which is effective in treating pain and at the same timehave one or more of the following advantages: a relative low maximalserum concentration of the opioid and pain relieving effect, relativedecreased average serum concentrations and pain relieving effect,minimal concentrations of opioid and pain relieving effect. Each ofthese factors may be associated with a minor risk of side effects. Thisconclusion is be supported by a less frequently reported side effects bythe patients receiving such a composition in a clinical study comparingcontrolled release compositions having a non-zero order dissolutionprofile. Adverse events to be reported in such study include sedation,nausea, dizziness, vertigo, obstipation, urine retention, itching,perspiration, dry mouth, It is generally acknowledged that the most ofthe broad variety of adverse effects of morphine correlate with thedosage.

Accordingly, a limitation of the maximal concentration as well as theduration of a sufficient concentration is of great benefit for everypatient. On the other hand, in chronic pain treatment with morphine, toolow concentrations will immediately result in the need for additionalrescue medication leading to an increase in the overall dosage, and inthe end, to a higher incident of dose dependent side effects. Also inthis respect, a formulation according to the present invention isexpected to result in the decrease in maximal concentration without adecrease in pain relieving effect. If the controlled release compositionis not optimal, the final treatment regimen for the patient includingthe rescue medication may resemble an ordinary treatment and only fewbenefits are obtained.

With respect to safety and side effects, many controlled releaseformulations are only compared with immediate release formulations. Theformulation according to the present invention addresses all theproblems of a sustained release formulation by releasing a steady andaccurately predictable flow of the opioid.

The term “opioid” as used herein denotes a group of active substancesthat are, to a varying degree, opium- or morphine-like in theirproperties. The term includes natural and synthetic opioids as well asactive metabolites such as, e.g. morphine 6-glucuronide, morphine3-glucuronide, and mixtures thereof. Pharmaceutically acceptable salts,complexes, solvates and anhydrates thereof, and mixtures thereof arealso within the definition of opioids.

In those cases, where the active substance is dispersed in the matrix,it is present in any of its crystalline, polymorphous or amorphous formsor mixtures thereof.

In specific embodiments, the active substance may at least partially bepresent in solid form in the dispersion, i.e. some of the activesubstance may be dissolved in the polymer (such as, e.g., polyethyleneoxide) provided that at least a part is still present on solid form.

In the pharmaceutical technology (and in the present context), the term“solid dispersion” also embraces semi-solid dispersions. By the term isunderstood the finely dispersed distribution of one or more solids, e.g.an active substance like morphine, in an inert solid or semi-solidcarrier. The active substance may be present in molecular dispersedform, i.e. as a solid solution, in fine crystalline dispersed form, in aglassy amorphous phase or dispersed as a fine amorphous powder. Eutecticmixtures, i.e. crystalline structures of active substances and carriersare also encompassed in the definition of “solid dispersions”. Normally,the mean particle size is used to classify dispersed system. A colloidaldispersion is when the dispersed phase has a particle size between about1 and about 1000 nm and a coarsely dispersion has a mean particle sizeof at least about 1000 nm and a molecular dispersion has a particle sizebelow about 1 nm. Combinations between the various states are verylikely and the most dominating character can be determined by X-raydiffraction spectra or differential thermoanalysis.

In specific aspects of the present invention some of the activesubstance may be present in a molecular dispersion such as, e.g., in theform of a solid or semi-solid solution.

In a preferred aspect of the invention, a composition comprises morphinethat at least partially is present in amorphous form with a meanparticle size of at least about 0.01 μm such as, e.g., from about 0.01μm to about 500 μm, from about 0.05 μm to about 500 μm, from about 0.1μm to about 500 μm, from about 0.5 μm to about 500 μm, about 1 μm toabout 500 μm, typically from about 0.5 μm to about 300 μm, moretypically from about 1 μm to about 200 μm, especially from about 1 μm toabout 100 μm.

In general, the opioids are readily absorbed from the gastrointestinaltract after oral administration. Many opioids like e.g. morphine aresubject to a first-pass metabolism in the liver. The half-life ofmorphine is about 1.5 to 2 hours, but morphine is metabolised to activemetabolites, which have a longer half-life. The average duration ofaction of a single dose of 10 mg of e.g. oral morphine is about 4-5hours (given as a plain tablet composition).

The dosage of the opioid(s) contained in a controlled releasecomposition according to the invention depends on the particular opioidin question. With respect to morphine an amount corresponding to fromabout 5 to about 800 mg of morphine sulfate is suitable. Alternatively,the dosage form (i.e. the composition) may contain a molar equivalentamount of another morphine salt (i.e. the hydrochloride etc.).

Examples of opioids suitable for use in a composition according to thepresent invention are:

Alfenlanil, allylprodine, alphaprodine, aniloridine, benzylmorphine,bezitramide, buprenorphine, butophanol, clonitazene, codeine,cyclazocine, desomorphine, dextromoramide, dezocine, diapromide,dihydrocodeine, dihydromorphine, dimenoxadol, dimephetanol,dimethylthiambutene, dioxaphetyl butyrale, dipipanone, optazocino,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazone,fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, dextropropoxyphene, kelobemidone, levallorphan,levorphanol, levophenacylmorphan, lofentani, meperidine, moptazinol,metazocine, methadone, metopon, morphine, morphine 6-glucuronide,morphine 3-glucuronide, myrophine, nalbuphine, narccine, nicomorphine,norlevorphanol, normethadone, nalorphine, normorphine, norpipanone,opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone,phenomorphan, phenazocine, phenoperidine, piminodine, piritramide,propheptazine, promedol, properidine, propiram, propoxyphene,sufentanil, tilidine, tramadol, and pharmaceutically acceptable salts,complexes, solvates or anhydrates thereof, and mixtures thereof.

The term “pharmaceutically acceptable salts” of an opiod includes alkalimetal salts such as, e.g., sodium or potassium salts, alkaline earthmetal salts such as, e.g., calcium and magnesium salts, and salts withorganic or inorganic acid like e.g. hydrochloric acid, hydrobromic acid,nitric acid, sulfuric acid, phosphoric acid, citric acid, formic add,maleic acid, succinic acid, tartaric acid, methansulphonic acid,toluenesulphonic acid etc.

The term “solvates” includes hydrates or solvates wherein other solvatesthan water are involved such as, e.g., organic solvents like chloroformand the like.

Furthermore, the opiod such as morphine may be in any of itscrystalline, polymorphous or amorphous forms.

The present inventors have applied a novel method for controlling therelease of an active substance from a pharmaceutical composition. Themethod involves controlling the release of at least one therapeutically,prophylactically and/or diagnostically active substance into an aqueousmedium by erosion of at least one surface of a pharmaceuticalcomposition comprising

i) a matrix composition comprising a) polymer or a mixture of polymers,b) an active substance and, optionally, c) one or more pharmaceuticallyacceptable excipients, and

ii) a coating having at least one opening exposing at the one surface ofsaid matrix, the coating comprising

-   -   a) a first cellulose derivative which has thermoplastic        properties and which is substantially insoluble in the aqueous        medium in which the composition is to be used.        and at least one of    -   b) a second cellulose derivative which is soluble or dispersible        in water,    -   c) a plasticizer, and    -   d) a filler,        the method comprising adjusting the concentration and/or the        nature of the ingredients making up the matrix composition in        such a manner that the diffusion rate of the aqueous medium into        the matrix composition corresponds to about 100%±30% such as,        e.g. about 100%±25%, about 100%±20%, about 100%±15% or about        100%±10% or about 100% of the dissolution rate of the matrix        composition so as to obtain a zero order release of at least        about 60% w/w such as, e.g. at least about 65% w/w at least        about 70% w/w, at least about 75% w/w, at least about 80% w/w,        at least about 85% w/w, at least about 90% w/w, at least about        95% w/w or at least about 97 or 98% w/w of the active substance        from the pharmaceutical composition when subject to an in vitro        dissolution test as described herein.

Details concerning the method and the pharmaceutical compositions aredescribed herein.

In a specific embodiment of the invention the polymer mentioned under a)is a substantially water soluble or crystalline polymer or a mixture ofsubstantially water soluble and/or crystalline polymers.

Controlled Release

During the last decades many different systems for modifying the releaseof an active drug substance from a pharmaceutical composition have beendeveloped. Most of them aim at obtaining a zero or a first order releaserate of the active substance from the composition. Zero order releaserate (i.e. constant release of the active substance with time) seems tobe very difficult to obtain from a pharmaceutical composition. Thepresent invention is based on a polymeric matrix composition, which isconstrued to deliver the active substance in a zero order releasemanner. The present invention is a further development based on theApplicant's previously described drug delivery systems, see e.g. EP-B-0406 315, EP-B-0 493 513, EP-B-0 740 310 and WO 99/51208 the disclosureof which is hereby incorporated by reference.

In particular, it has surprisingly been found that it is possible toobtain zero order release from a polymeric matrix composition withoutany content of a water dispersible or water soluble surface active agentor a mixture of such surface active agents which has at least one domainwhich is compatible with the polymer in the polymer matrix compositionand at least one other domain which is substantially lipophilic andwhich has a melting point that is lower than the polymer used in thepolymeric matrix composition. The presence of such a substance (e.g.like PEG 400 monostearate or PEG 2000 monostearate) has beencontemplated to function as a so-called repair medium. Such a repairmedium has a substantially hydrophilic domain, which gives it affinityto the (crystalline) polymeric phase, thereby filling in domains betweengrains and cracks in the polymer matrix and reducing the water affinityof these domains and in the polymer matrix itself. Water diffusion inthe interface between the polymer crystals is thereby substantiallyeliminated, thus substantially limiting diffusion of water into thecomposition to the surface layer of the matrix, so that erosion of thecomposition is predominantly effected by the dissolving action of theaqueous phase on a surface or surfaces of the composition exposed to theaqueous medium. In other words a repair medium seems to prevent thediffusion of water in the polymer matrix composition.

However, in certain cases, the present inventors have observed thatinclusion of a water soluble surface active agent has a negative impacton the mobility and/or stability of a composition.

The present inventors have found that it is possible to obtain a zeroorder release from a polymer matrix composition although water may beable to diffuse into the matrix. When water diffuse into the polymermatrix composition a resulting boundary layer (or swelling layer) can beformed at the surface of the matrix composition, which is exposed to theaqueous medium. In general the diffusion of an active substance throughsuch a boundary layer is important for the release of an activesubstance and, accordingly, the thickness of the boundary layer isimportant for the release rate. However, the present inventors havefound that it is possible to eliminate or substantially eliminate theimpact of the boundary layer on the release rate of the active substancefrom a polymer matrix composition by ensuring that the thickness of theboundary layer is relatively small and/or that the release of the activesubstance from a polymer matrix composition is governed by erosion ofthe composition and the diffusion of the active substance through theboundary layer, if any, has no or only a small impact on the overallrelease rate.

The present inventors have found that when water is allowed to diffuseinto a polymer matrix composition zero order release is obtained whenthe release rate is governed or controlled by erosion of a constantsurface area per time unit. In order to ensure that the erosion of thepolymer matrix composition is the predominant release mechanism, theinventors have found that it is necessary to provide a polymer matrixcomposition which has properties that ensures that the diffusion rate ofwater into the polymer matrix composition substantially corresponds tothe dissolution rate of the polymer matrix composition into the aqueousmedium. Thus, by adjusting the nature and amount of constituentscontained in the polymer matrix composition along this line the presentinventors have obtained polymer matrix compositions, which release theactive substance by a zero order release mechanism. The compositionsemployed are coated in such a manner that at least one surface isexposed to the aqueous medium and this surface has a substantiallyconstant or controlled surface area during erosion. In the presentcontext controlled surface area relates to a predetermined surface areatypically predicted from the shape of the coat of the unit dosagesystem. It may have a simple uniform cylindrical shape or thecylindrical form can have one or more tapered ends in order to decrease(or increase) the initial release period.

Accordingly, the present invention provides a method for controlling therelease of at least one therapeutically, prophylactically and/ordiagnostically active substance into an aqueous medium by erosion of atleast one surface of a pharmaceutical composition comprising

i) a matrix composition comprising a) polymer or a mixture of polymers,b) an active substance and, optionally, c) one or more pharmaceuticallyacceptable excipients, and

ii) a coating having at least one opening exposing at the one surface ofsaid matrix, the coating comprising

-   -   a) a first cellulose derivative which has thermoplastic        properties and which is substantially insoluble in the aqueous        medium in which the composition is to be used,        and at least one of    -   b) a second cellulose derivative which is soluble or dispersible        in water,    -   c) a plasticizer, and    -   d) a filler,        the method comprising adjusting the concentration and/or the        nature of the ingredients making up the matrix composition in        such a manner that the diffusion rate of the aqueous medium into        the matrix composition corresponds to about 100%±30% such as,        e.g. about 100%±25%, about 100%±20%, about 100%±15% or about        100%±10% or about 100% of the dissolution rate of the matrix        composition so as to obtain a zero order release of at least        about 60% w/w such as, e.g. at least about 65% w/w at least        about 70% w/w, at least about 75% w/w, at least about 80% w/w,        at least about 85% w/w, at least about 90% w/w, at least about        95% w/w or at least about 97 or 98% w/w of the active substance        from the pharmaceutical composition when subject to an in vitro        dissolution test as described herein.

As mentioned above, in a specific embodiment of the invention, thepolymer a) is a substantially water soluble or crystalline polymer or amixture of substantially water soluble and/or crystalline polymers.

By use of such a method it is possible already during the developmentalwork to test various polymer matrix compositions with respect todiffusion rate of water into the composition and to dissolution rate ofthe polymer matrix composition in an aqueous medium. Based on suchresults adjustment of e.g. the concentration and/or nature of theindividual constituents in the composition may be performed until thediffusion rate balance the dissolution rate. In such a manner, arelatively simple instrument has been provided in order to ensure a zeroorder release rate from the final composition.

In another aspect, the invention relates to a pharmaceutical compositionfor controlled release of at least one therapeutically, prophylacticallyand/or diagnostically active substance into an aqueous medium by erosionof at least one surface of the composition, the composition comprising

i) a matrix composition comprising a) a polymer or polymers, b) anactive substance and, optionally, c) one or more pharmaceuticallyacceptable excipients, and

ii) a coating having at least one opening exposing at the one surface ofsaid matrix, the coating comprising

-   -   a) a first cellulose derivative which has thermoplastic        properties and which is substantially insoluble in the aqueous        medium in which the composition as to be used,        and at least one of    -   b) a second cellulose derivative which is soluble or dispersible        in water,    -   c) a plasticizer, and    -   d) a filler,        and the concentration and/or the nature of the ingredients        making up the matrix composition has been adjusted in such a        manner that the diffusion rate of the aqueous medium into the        matrix composition corresponds to about 100%±30% such as, e.g.        about 100%±25%, about 100%±20%, about 100%±15% or about 100%±10%        or 100% of the dissolution rate of the matrix composition so as        to obtain a zero order release of at least about 60% w/w such        as, e.g. at least about 65% w/w at least about 70% w/w, at least        about 75% w/w, at least about 80% w/w, at least about 85% w/w,        at least about 90% w/w, at least about 95% w/w or at least about        97 or 98% w/w of the active substance from the pharmaceutical        composition when subject to an in vitro dissolution test as        described herein.

As mentioned before, in a specific embodiment, the polymer a) is asubstantially water soluble or crystalline polymer or a mixture ofsubstantially water soluble and/or crystalline polymers.

Matrix Composition

The pharmaceutical composition according to the invention comprises amatinx composition comprising

-   -   a) a polymer or a mixture of polymers.    -   b) an active substance and, optionally,    -   c) one or more pharmaceutically acceptable excipients.

In a specific embodiment, the polymer is a substantially water solubleor crystalline polymer or a mixture of substantially water solubleand/or crystalline polymers.

Polymers

Suitable polymers for use according to the invention typically comprisesa polyglycol, e.g. in the form of a homopolymer and/or a copolymer. In aspecific embodiment the polymer is substantially water soluble orcrystalline polymer or a mixture of substantially water soluble and/orcrystalline polymers. Suitable polymers for use in a compositionaccording to the invention are polyethylene oxides and/or blockcopolymers of ethylene oxide and propylene oxide. Polyethylene oxideswhich are suitable for use in the matrix composition are those having amolecular weight of from about 20,000 daltons, such as, e.g., from about20.000 to about 700,000 daltons, from about 20,000 to about 600,000daltons, from about 35,000 to about 500,000 daltons, from about 35,000to about 400,000 daltons, from about 35.000 to about 300,000 daltons,from about 50,000 to about 300,000 daltons, such as, e.g. about 35,000daltons, about 50,000 daltons, about 75,000 daltons, about 100,000daltons, about 150.000 daltons, about 200,000 daltons, about 250,000daltons, about 300,000 daltons or about 400,000 daltons.

A particular suitable polyethylene oxide as one, which in itself has asuitable balance between the diffusion rate of water into the polymerand a dissolution rate of the polymer. Suitable examples arepolyethylene oxides having a molecular weight of about 35,000 daltons,about 50,000 daltons, about 100,000 daltons, about 200,000 daltons,about 300,000 daltons and about 400,000 daltons.

Typical block copolymers of ethylene oxide and propylene oxide maycomprise up to about 30% w/w of the propylene oxide based block, and hasa molecular weight of about 5,000 daltons, typically about 5,000 toabout 30,000 daltons such as, e.g. from about 8,000 to about 15,000daltons.

Polyethylene glycols (which when the molecular weight is above about20,000 is denoted polyethylene oxides) are mixtures of condensationpolymers of ethylene glycol.

The average molecular weight (MW) can be calculated from the followingequationMW=(56,110×2)/hydroxyl number

Where the hydroxyl number is defined as the number indicating the amountin mg of potassium hydroxide, which is equivalent to the acetic acid,which, by acetylation, is bound by 1 g of a substance.

Mixtures of PEO with different average molecular weights can be used inorder to obtain a PEO with a desirable average molecular weight. It isimportant to note that in such cases it is necessary to use the PEO,which have MW closest to the desired molecular weight. The individualamount of the two PEO necessary to obtain a PEO with a desired MW can becalculated from the hydroxyl number and the equation given above.

The polymer may have a melting point, which is above the bodytemperature of the human or animal in which the composition is to beused. Thus, the polymer(s) employed in the matrix composition willsuitably have a melting point of about 20-120° C. such as, e.g. fromabout 30 to about 100° C. or from about 40 to about 80° C.

Alternatively to a polymer of a polyglycol type as described above otherpolymers may be suitable for use in the matrix composition a). Thus, inother embodiments of the invention, the polymer is selected from one ormore of the following polymers: water soluble natural polymers such asglucomannan, galactan, glucan, polygalacturonic acid, polyxylane,polygalactomannans, rhanogalacturonan, polyxyloglycan, arabinogalactan,and starch; water soluble polymers such as PVA, PVB, methocel, EudragitL methyl ester and PHPV; biodegradable polymers such as PHA, and PLA;hydrogels, such as olyacrylic amid, and dextran: copolymers such aspolylactic acid with polyglycolic acid; and others such as alginate andpectins including low methylated or methoxylated pectins.

Active Substances

The method for controlling the release of an active system as disclosedherein can also be applied to other active substances than opioids.Thus, a pharmaceutical composition according to the invention maycomprise one or more active substances, i.e. substances, which aretherapeutically, prophylactically, diagnostically and/or biologicallyactive substance. The term “active substance” as used herein broadlyincludes any compound, or mixture thereof, that can be delivered fromthe composition to produce a beneficial result. The active andbeneficial agents include pesticides, herbicides, germicides, biocides,algicides, rodenticides, fungicides, insecticides, antioxidants, planthormone promoters, plant growth inhibitors, preservatives,disinfectants, sterilization agents, catalysts, chemical reactants,fermentation agents, food supplements, nutrients, cosmetics,therapeutically active substances (drugs), vitamins, sex sterilants,fertility inhibitors, fertility promoters, air purifiers, microorganismattenuators, ecological agents and other agents that benefit theenvironment in which they are used.

In the present context the term “drug substance” includes anyphysiologically or pharmacologically active substance that produces alocalized or systemic effect in animals, in particular in mammals,including humans and primates. Other animals include domestic household,sport or farm animals such as sheep, goats, cattle, horses and pigs,laboratory animals such as mice, rats and guinea pigs, fishes, avians,reptiles and zoo animals. The term “therapeutically, prophylacticallyand/or diagnostically active substance” includes the term drug substancewithin its meaning.

In the present context, the term “ecological agent” denotes anon-therapeutic substance that has a biological effect on plants oranimals in the environment. An ecological agent may be a pesticide, suchas an insecticides or herbicide, a fertilizer a pheromone, a plantgrowth hormone or the like.

The active substance or substances included in a pharmaceuticalcomposition of the invention may be selected from many therapeuticcategories, in particular from substances which may advantageously beadministered orally, rectally, vaginally, or administered to a bodycavity (e.g. the urinary bladder, kidney pelvis, the gall bladder, theuterus, a central nervous system cavity,infectious/malignant/post-operative cavities, etc.).

Examples of such substances are hypnotics, sedatives, tranquilizers,anti-convulsants, muscle relaxants, analgesics, anti-inflammatory,anaesthetics, anti-spasmodics, anti-ulcer-agents, anti-parasitics,anti-microbials, anti-fungal, cardiovascular agents, diuretics,cytostatics, anti-neoplastic agents, anti-viral agents, anti-glaucomaagents, anti-depressants, sympathomimetics, hypoglycaemics, diagnosticagents, anti-cough, physic energizers, anti-parkinson agents, localanesthetics, muscle contractants, anti-malarials, hormonal agents,contraceptives, anorexic, anti-arthritic, anti-diabetic,anti-hypertensive, anti-pyretic, anti-cholingergic, bronchodilator,central nervous system, inotropic, vasodilator, vasoconstrictor,decongestant, hematine, iron salts and complexes, electrolytesupplement, germicidal, parasympathetolytic, parasympathethomimetic,antiemetic, psychostimulant, vitamin, beta-blockers, H-2 blocker, beta-2agonist, counterirritants, coagulating modifying agents, stimulants,anti-hormones, drug-antagonists, lipid-regulating agents, uricosurics,cardiac glycosides, ergots and derivatives thereof, expectorants,muscle-relaxants, anti-histamines, purgatives, contrastmaterials,radiopharmaceuticals, imaging agents, anti-allergic agents.

Examples of specific active substances suitable for use in a compositionof the invention are:

Carvedilol, morphine, diclofenac, nifedipine, calcitonin, rivastigmine,methylphenidate, fluoroxetine, rosiglitazone, prednison, prednisolone,codeine, ethylmorphine, dextromethorphan, noscapine, pentoxivorine,acetylcysteine, bromhexine, epinephrine, isoprenaline, orciprenaline,ephedrine, fenoterol, rimiterol, ipratropium, cholinetheophyllinate,proxiphylline, bechlomethasone, budesonide, deslanoside, digoxine,digitoxin, disopyramide, proscillaridin, chinidine, procainamide,mexiletin, flecainide, alprenolol, proproanolol, nadolol, pindolol,oxprenolol, labetalol, timolol, atenol, pentaentrityltetranitrate,isosorbiddinitrate, isosorbidmononitrate, niphedipin, phenylamine,verapamil, diltiazem, cyclandelar, nicotinylalcholhol,inositolnicotinate, alprostatdil, etilephrine, prenalterol, dobutamine,dopamine, dihydroergotamine, guanetidine, betanidine, methyldopa,reserpine, guanfacine, trimethaphan, hydralazine, dihydralazine,prazosine, diazoxid, captopril, nifedipine, enalapril, nitroprusslde,bendroflumethiazide, hydrochlorthiazide, metychlothiazide, polythiazide,chlorthalidon, cinetazon, dopamide, mefruside, metholazone, bumelanide,ethacrynacide, spironolactone, amiloride, chlofibrate, nicotinic add,nicheritrol, brompheniramine, cinnarizine, dexchlorpheniramine,clemastine, antazoline, cyproheptadine, proethazine, cimetidine,ranitidine, sucralfat, papaverine, moxaverine, atropin, butylscopolamin,emepron, glucopyrron, hyoscyamine, mepensolar, methylscopolamine,oxiphencydimine, probanteline, terodilin, sennaglycosides,sagradaextract, dantron, bisachodyl, sodiumpicosulfat, etulos,diphenoixylate, loperamide, salazosulfapyridine, pyrvin, mebendazol,dimeticon, ferrofumarate, ferrosuccinate, ferritetrasemisodium,cyanochobalamine, folid acid heparin, heparin co-factor, diculmarole,warfarin, streptokinase, urokinase, factor VIII, factor IX, vitamin K,thiopeta, busulfan, chlorambucil, cyclophosphamid, melfalan, carmustin,mercatopurin, thioguanin, azathioprin, cytarabin, vinblastin,vinchristin, vindesin, procarbazine, dacarbazine, lomustin, estramustin,teniposide, etoposide, cisplatin, amsachrin, aminogluthetimid,phosphestrol, medroxiprogresterone, hydroxiprogesterone, megesterol,noretisteron, tamoxiphen, cidosporin, sulfosomidine, bensylpenicillin,phenoxymethylpenicillin, dicdoxacillin, cloxacillin, flucoxacillin,ampicillin, amoxicillin, pivampicillin, bacampicillin, piperacillin,mezlocillin, mecillinam, pivmecillinam, cephalotin, cephalexin,cephradin, cephadroxil, cephador, cefuroxim, cefotaxim, ceftazidim,cefoxitin, aztreonam, imipenem, cilastatin, tetracycline, lymecydine,demedocycline, metacydine, oxitetracydine, doxycydine, chloramphenicol,spiramycin, fusidic acid, lincomycin, clindamycin, spectinomycin,rifampicin, amphotericin B, griseofulvin, nystatin, vancomycin,metronidazole, tinidazole, trimelhoprm, norfloxacin, salazosulfapyridin,aminosalyl, isoniazid, etambulol, nitrofurantoin, nalidixic acid,metanamine, chloroquin, hydroxichloroquin, tinidazol, ketokonazol,acyclovar, interferon idoxuridin, retinal, tiamin, dexpantenol,pyridoxin, folic acid, ascorbic acid, tokoferol, phytominadion,phenfluramin, corticotropin, tetracosactid, tyrotropin, somatotoprin,somatrem, vasopressin, lypressin, desmopressin, oxytocin,chlonongoradotropin, cortison, hydrocortisone, fluodrocortison,prednison, prednisolon, fluoximesteron, mosterolon, nandrolon,stanozolol, oximetolon, cyproteron, levotyroxin, liotyronin,propylthiouracil, carbimazol, tiamazol, dihydrotachysterol,alfacalcidol, calcitirol, insulin, tolbutamid, chlorpropamid, tolazamid,glipizid, glibendamid, phenobarbital, methyprylon, pyrityldion,meprobamat, chlordiazepoxid, diazepam, nitrazepam, oxazepam,dikaliumclorazepat, lorazepam, flunitrazepam, alprazolam, midazolam,hydroxizin, chlometiazol, propionmazine, alimemazine, chlorpromazine,tevomepromazine, acetophenazine, fluphenazine, perphenazine,prochlorperazine, trifluoperazine, dixyrazine, thiodirazine, periciazin,chloprothixene, zuciopentizol, flupentizol, thithixen, haloperidol,trimipramin, opipramol, chlomipramin, desipramin, lofepramin,amitriptylin, nortriptylin, protriptylin, maptrotilin, caffeine,cinnarizine, cydizine, dimenhydinate, meclozine, prometazine,thiethylperazine, metoclopramide, scopolamine, phenobarbital,phenytoine, elhosuximide, primidone, carbamazepine, chlonazepam,orphenadrine, atropine, bensatropine, biperiden, metixene, procylidine,levodopa, bromocriptin, amantadine, ambenon, pyridostigmine,synstigmine, disulfiram, morphine, codeine, pentazocine, buprenorphine,pethidine, phenoperidine, phentanyl, methadone, piritramide,dextropropoxyphene, ketobemidone, acetylsalicylic acid, phenazone,phenylbutazone, azapropazone, piroxicam, ergotamine, dihydroergotamine,cyproheptadine, pizitifen, flumedroxon, allopurinol, probenecid,sodiummaurothiomalate auronofin, penicillamine, estradiol,estradiolvalerianate, estriol, ethinylestradiol, dihydrogesteron,lynestrenol, medroxiprogresterone, noretisterone, cyclophenile,clomiphene, levonorgestrel, mestranol, omidazol, tinidazol, ekonazol,chlotrimazol, natamycine, miconazole, sulbentin, methylergotamine,dinoprost, dinoproston, gemeprost, bromocriptine, phenylpropanolamine,sodiumchromoglicate, azetasolamide, dichlophenamide, betacarotene,naloxone, calciumfolinate, in particular clonidine, thephylline,dipyradamol, hydrochlothiazade, scopolamine, indomethacine, furosemide,potassium chloride, morphine, ibuprofen, salbutamol, terbutalin,sulfonyfurea, metformin, insulin, calcitonin, glucagons-like peptide-1,or combinations thereof.

The active substance can be in various forms, such as unchargedmolecules, molecular complexes, crystalline forms, amorphous form,polymorphous form, solvates, anhydrates, pharmacologically acceptablesalts such as a hydrochloride, hydrobromide, sulfate, laurylate,palmitate, phosphate, nitrite, nitrate, borate, acetate, maleate,tartrate, oleate, and salicylate. For acidic active substance, salts ofmetals, amines amino acids or organic cations, quaternary ammoniums, canbe used. Derivatives of active substances such as esters, ethers andamides which have solubility characteristics suitable for use herein canbe used alone or mixed with other drugs. After release of the derivativefrom the drug delivery system it may be converted by enzymes, hydrolysedby body pH or other metabolic processes to the parent drug or to anotherbiologically active form.

A pharmaceutical composition of the invention may in addition besuitable for the delivery of polypeptides, for example hormones, enzymessuch as lipases, proteases, carbohydrates, amylases, lactoferrin,lactoperoxidases, lysozymes, nanoparticles, etc., and antibodies. Thecomposition may also be employed for the delivery of microorganisms,either living, attenuated or dead, for example bacteria, e.g.gastrointestinal bacteria such as streptococci, e.g. S. faecium,Bacillus spp. such as B. subtilis and B. licheniformis, lactobacteria,Aspergillus spp., bifidogenic factors, or viruses such as indigenousvira, enterovira, bacteriophages, e.g. as vaccines, and fungi such asbaker's yeast, Saccharomyces cerevisiae and fungi imperfecti. Apharmaceutical composition of the invention may also be used for thedelivery of active agents in specialized carriers such as liposomes,cyclodextrines, nanoparticles, micelles and fats.

A further use for which a composition of the invention is suited is thedelivery of active substances to animals. Examples of such activesubstances for veterinary use are antiparasitics, corticosteroids,antibiotics, antiinflammatory agents, growth promoters and permittants,antifungals and antihelmintics.

A pharmaceutical composition of the invention is designed to release theactive substance in a controlled manner such as by a zero order releasemechanism. Accordingly, the composition is also suitable for acontrolled release of an active substance. In the present context thetem “controlled release” is used to designate a release a desired rateduring a predetermined release period. Terms like “modified”, “delayed”,“sustained”, “prolonged”, “extended” etc. release are in the presentcontext synonyms to the term “controlled release”.

In an embodiment of the invention, the active substance is apharmaceutically active powder. The powder typically has a particle sizeof from about 0.1 μm to about 500 μm, typically from about 0.5 μm toabout 300 μm, more typically from about 1 μm to about 200 μm, especiallyfrom about 5 μm to about 100 μm.

A pharmaceutical composition according to the invention is—due to thepossibility of designing the composition in such a manner that i) a zeroorder release is obtained and ii) a controlled release during apredetermined time period is obtained—suitable for use for water solubleas well as slightly soluble or insoluble active substances. However, itis contemplated that a composition is especially suitable for use whenthe at least one therapeutically, prophylactically and/or diagnosticallyactive substance has a solubility of at the most about 3 mg/ml such as,e.g. at the most about 1 mg/ml, at the most about 0.1 mg/ml, at the mostabout 0.05 mg/ml such as, e.g. at the most about 0.001 mg/ml in water atambient temperature and/or a prolonged release of the active substanceis desired in order to obtain i) a prolonged residence time within thebody after administration, ii) a reduced peak plasma concentration inorder to avoid peak related side effects, iii) reduced frequency ofadministration in order e.g. to obtain a better patient compliance, etc.

To this end it seems that substantially hydrophobic active substancestend to result in a decrease in the erosion rate of the matrixcomposition. Substantially hydrophilic or water-soluble activesubstances seem to have the opposite effect. i.e. they tend to result ina faster erosion of the matrix.

The at least one therapeutically, prophylactically and/or diagnosticallyactive substance will suitably be present in an amount of up to about70%, typically up to about 60% or up to about 50%, by weight of thematrix composition. An active substance content of about 60% iscontemplated to be the maximum content, which still allows for asufficient content of the polymer and, when relevant, thepharmaceutically acceptable excipient in the composition. The activesubstance may, on the other hand, be present in the composition in muchsmaller amounts, depending on the nature and potency of the activesubstance in question.

Pharmaceutically Acceptable Excipients

Diffusion and Dissolution Adjusters

As already discussed above, it is important that a composition accordingto the invention releases at least most of the active substance by azero order release mechanism. One aspect of research aboutcontrolled-release delivery systems involves designing a system, whichproduces steady-state plasma drug levels. The release of activesubstance fraom such systems is also referred to as zero-order drugrelease kinetics. To meet this objective, numerous design variationshave been attempted, and their major controlling mechanisms includediffusion/dissolution.

The release rate of a dissolved or dispersed active substance from apolymeric matrix composition introduced in a specific environment,strongly depends on the nature of the diffusion and sorption processesinvolving the polymer/environment system and the polymer/activesubstance system.

The active substance release data may be analysed using Eq. 1 and Eq. 2where M_(t)/M_(∞) is the fractional drug release, t is the release time,k is a kinetic constant characteristics of the drug/polymer system,C_(d) is the tracer loading concentration and n is an exponent whichcharacterisers the mechanism of release of the tracers.

$\begin{matrix}{\frac{M_{t}}{M_{\infty}} = {{k \cdot}t^{n}}} & \left( {{Eq}.\mspace{14mu} 1} \right) \\{\frac{\mathbb{d}M_{t}}{A \cdot {\mathbb{d}t}} = {{n \cdot C_{d} \cdot k \cdot}t^{n - 1}}} & \left( {{Eq}.\mspace{14mu} 2} \right)\end{matrix}$

Clearly, a desirable mechanism for many applications is that which leadsto n=1. This characterizes zero-order behaviour. The table belowsummarizes the general dependence of n on the diffusion mechanism.

Diffusinal release solute release Overall Solute diffusion timedependence of Exponent (n) mechanism rate (dM_(t)/d_(t)) 0.5 Fickiandiffusion t^(−0.5) 0.5 < n < 1.0 Anomalous (non Fickian) t^(n−1)diffusion 1.0 Case II Transport Zero-order (time independent) releasen > 1.0 Super Case II transport t^(n−1)

In the case of PEO matrices, the solubility of the polymer can alter thecharacteristics of the penetrated layer, leading to different behavioursin systems presenting different dissolution features. To control therelease of the active agent, them should be a balance between diffusionof the active agent and solubilization of the polymer matrix. Thediffusivity of the drug through the matrix, the swelling of the polymer,and its solubilization rate may be biased by changing the molecularweight of the polymer or blending polymer fractions with differentmolecular weights.

In the following is given examples on suitable excipients that may beadded in order to adjust the balance between diffusion and dissolutionso as to obtain zero order release rate. The pharmaceutically acceptableexcipients suitable for establishing the above-mentioned desiredbalance, are in the present context also denoted DDAs (Diffusion andDissolution Adjusters).

Thus, the matrix composition may also comprise one or morepharmaceutically acceptable excipients (DDAs). The function of the atleast one pharmaceutically acceptable excipient is to establish thedesired balance between on the one hand the diffusion rate of water intothe matrix composition and on the other hand the dissolution rate of thematrix composition in an aqueous medium such as, e.g., water. Asexplained above, a zero order release rate is obtained if that thediffusion rate of the aqueous medium into the matrix compositioncorresponds to about 100%±30% such as, e.g. about 100%±25%, about100%±20%, about 100%±15% or about 100%±10% or about 100% of thedissolution rate of the matrix composition. By the term “zero orderrelease” is meant that the release takes place so as to obtain a zeroorder release of at least about 60% w/w such as, e g. at least about 65%w/w, at least about 70% w/w, at least about 75% w/w, at least about 80%w/w, at least about 85% w/w, at least about 90% w/w, at least about 95%w/w or at least about 97 or 98% w/w of the active substance from thepharmaceutical composition when subject to an in vitro dissolution testas described herein.

In general a test for diffusion of water into the matrix composition anda test for the dissolution of the matrix composition in an aqueousmedium are performed using a matrix composition having the desired shapeand being prepared analogous to the matrix composition in the finalcomposition. This means that when the final composition is prepared bye.g. injection moulding then the matrix composition to be tested withrespect to diffusion and dissolution behaviour is also prepared byinjection moulding.

There may be cases where it is not necessary to adjust the matrixcomposition by adding a pharmaceutically acceptable excipient. Suchcases are e.g. when the polymer employed in itself has the desiredproperties with respect to diffusion of water and dissolution ofpolymer.

In the experimental section herein examples are given showing that ithas been possible to obtain the desired zero order release when apharmaceutically acceptable excipients has been incorporated into thematrix composition.

Without being bound by any theory it is contemplated that in those caseswhere a slightly or insoluble active substance is employed then it maybe necessary to circumvent the effect from the active substance (withrespect to diffusion and/or dissolution of the matrix composition) byadding a very soluble pharmaceutically acceptable excipient.Accordingly, it is contemplated that when the at least onetherapeutically, prophylactically and/or diagnostically active substancehas a solubility of at the most about 3 mg/ml such as, e.g. at the mostabout 1 mg/ml, at the most about 0.1 mg/ml, at the most about 0.05 mg/mlsuch as, e.g. at the most about 0.001 mg/ml in water at ambienttemperature then the pharmaceutically acceptable excipient, if present,typically has a solubility of at least 1 mg/ml such as, e.g. at leastabout 3 mg/ml, at least about 5 mg/ml, at least about 10 mg/ml, at leastabout 25 mg/ml or at least about 50 mg/ml in water at ambienttemperature.

Vice versa, it is contemplated that in those cases where a very solubleactive substance is employed then it may be necessary to circumvent theeffect from the active substance (with respect to diffusion and/ordissolution of the matrix composition) by adding a slightly or insolublepharmaceutically acceptable excipient. Accordingly, it is contemplatedthat when the at least one therapeutically, prophylactically and/ordiagnostically active substance has a solubility of at least about 3mg/ml such as, e.g., at least about 5 mg/ml, at least about 10 mg/ml, atleast about 20 mg/ml, at least about 50 mg/ml or at least about 100mg/ml in water at ambient temperature, then the pharmaceuticallyacceptable excipients typically has a solubility of at the most about 3mg/ml such as, e.g., at the most about 1 mg/ml, at the most about 0.1mg/ml, at the most about 0.05 mg/ml such as, e.g. at the most about0.001 mg/ml in water at ambient temperature.

There may situations, however, where it also may be suitable toincorporate water-soluble substances (and/or water-insoluble substances)as DDA's irrespective of the solubility of the active substance.

Furthermore, in those cases where the active substance employed has alow solubility in acidic medium, it is contemplated that an inorganic ororganic base or substance having an alkaline reaction in aqueousenvironment is employed as a DDA.

Analogous, in those cases where the active substance employed has a lowsolubility in alkaline medium, it is contemplated that an inorganic ororganic acid or substance having an acidic reaction in aqueousenvironment is employed as a DDA.

However, other factors than the solubility in water play a role in theerosion process and therefore there may be situations where such factorsdominate the solubility factor and then the above-given combinations maybe of minor importance.

Suitable pharmaceutically acceptable excipients (DDAs) may be selectedfrom the group consisting of inorganic acids, inorganic bases, inorganicsalts, organic acids or bases and pharmaceutically acceptable saltsthereof, saccharides, oligosaccharides, polysaccharides, and celluloseand cellulose derivatives.

Alternatively or additionally, a suitable pharmaceutically acceptableexcipient is a mono-, di-, oligo, polycarboxylic acid or amino acidssuch as, e.g. acetic acid, succinic acid, citric acid, tartaric acid,acrylic acid, benzoic acid, malic acid, maleic acid, sorbic acid etc.,aspartic acid, glutamic acid etc.

Examples of suitable organic acids include acetic acid/ethanoic add,adipic acid, angelic acid, ascorbic acid/vitamin C, carbamic acid,cinnamic acid, citramalic acid, formic acid, fumaric acid, gallic acid,gentisic acid, glutaconic acid, glutaric acid, glyceric acid, glycolicacid, glyoxylic acid, lactic acid, levulinic acid, malonic acid,mandelic acid, oxalic acid, oxamic acid, pimelic acid, and pyruvic acid.

Examples of suitable inorganic acids include pyrophosphoric,glycerophosphoric, phosphoric such as ortho and meta phosphoric, boricacid, hydrochloric acid, and sulfuric acid.

Examples of suitable inorganic compounds include aluminium.

Examples of organic bases are p-nitrophenol, succinimide,benzenesulfonamide, 2-hydroxy-2cyclohexenone, imidazole, pyrrole,diethanolamine, ethyleneamine,tris (hydroxymethyl) aminomethane,hydroxyfamine and derivates of amines, sodium citrate, aniline,hydrazine.

Examples of inorganic bases include aluminium oxide such as, e.g.,aluminium oxide trihydrate, alumina, sodium hydroxide, potassiumhydroxide, calcium carbonate, ammonium carbonate, ammonium hydroxide,KOH and the like.

Suitable pharmaceutically acceptable salts of an organic acid is e.g. analkali metal salt or an alkaline earth metal salt such as, e.g. sodiumphosphate, sodium dihydrogenphosphate, disodium hydrogenphosphate etc.,potassium phosphate, potassium dihydrogenphosphate, potassiumhydrogenphosphate etc., calcium phosphate, dicalcium phosphate etc.,sodium sulfate, potassium sulfate, calcium sulfate, sodium carbonate,sodium hydrogencarbonate, potassium carbonate, potassiumhydrogencarbonate, calcium carbonate, magnesium carbonate etc., sodiumacetate, potassium acetate, calcium acetate, sodium succinate, potassiumsuccinate, calcium succinate, sodium citrate, potassium citrate, calciumcitrate, sodium tartrate, potassium tartrate, calcium tartrate etc.

A suitable inorganic salt for use in a matrix composition of theinvention is sodium chloride, potassium chloride, calcium chloride,magnesium chloride etc.

Examples of such excipients are glucose and other monosaccharides,ribose, arabinose, xylose, lyxose, allose, altrose, inosito, glucose,sorbitol, mannose, gulose, idose, galactose, talose, mannitol, fructose,lactose, sucrose, and other disaccharides, dextrin, dextran or otherpolysaccharides, amylose, xylan, cellulose and cellulose derivativessuch as, e.g. microcrystalline cellulose, methyl cellulose, ethylcellulose, ethylhydroxyethyl cellulose, ethylmethylcellulose,hydroxyethylcellulose, hydroxyethylmethyl cellulose, carboxymethylcellulose, hydroxypropyl cellulose, hydroxymethylpropyl cellulose,hydroxypropylmethyl cellulose, amylopectin, pectin, starch, sodiumstarch etc., kaolin, bentonit, acacia, alginic acid, sodium alginate,calcium alginate, gelatin, dextrose, molasses, extract of Irish moss,panwar gum, ghatti gum, mucilage of isapol husk, veegum, glycollate,magnesium stearate, calcium stearate, stearic acid, talc, titaniumdioxide, silicium dioxide, days, croscarmellose, gums, agar etc.

Other Ingredients in the Matrix Composition

The matrix composition may also contain other excipients as well, e.g.in order to improve the technical properties of the matrix compositionso that it may be easier to produce or in order to improve the stabilityof the composition.

A suitable pharmaceutically acceptable excipient for use in a matrixcomposition of the invention may be selected from the group consistingof fillers, diluents, disintegrants, glidants, pH-adjusting agents,viscosity adjusting agents, solubility increasing or decreasing agents,osmotically active agents and solvents.

Suitable excipients include conventional tablet or capsule excipients.These excipients may be, for example, diluents such as dicalciumphosphate, calcium sulfate, lactose or sucrose or other disaccharides,cellulose, cellulose derivatives, kaolin, mannitol, dry starch, glucoseor other monosaccharides, dextrin or other polysaccharides, sorbitol,inositol or mixtures thereof; binders such as acacia, sodium alginate,starch, gelatin, saccharides (including glucose, sucrose, dextrose andlactose), molasses, extract of Irish moss, panwar gum, ghatti gum,mucilage of isapol husk, carboxymethylcellulose, methylcellulose,veegum, larch arabolactan, polyethylene glycols, ethylcellulose, water,alcohols, waxes, polyvinylpyrrolidone such as, e.g., PVP K90 (may beused to improve mixing of the polymer with the other ingredients) ormixtures thereof; lubricants such as talc, magnesium stearate, calciumstearate, staeric acid, hydrogenated vegetable oils, sodium benzoate,sodium chloride, leucine, carbowax 4000, magnesium lauryl sulfate,colloidal silicon dioxide and mixtures thereof, disintegrants such asstarches, days, cellulose derivatives including crosscarmellose, gums,aligns, various combinations of hydrogencarbonates with weak acids (e.g.sodium hydrogencarbonatelltararic acid or citric acid) crosprovidone,sodium starch glycolate, agar, cation exchange resins, citrus pulp,veegum HV, natural sponge, bentonite or mixtures thereof; volatilesolvents such as alcohols, including aqueous alcohols, petroleumbenzine, acetone, ether or mixtures thereof; plasticizers such assorbitol and glycerine; and others such as cocoa butter, polyethyleneglycols or polyethylene oxides, e.g. with a molecular weight of about1,000-500.000 daltons, typically about 1,000-100,000 daltons, moretypically 1.000-50,000 daltons, especially about 1,000-10,000 daltons,in particular about 1,500-5,000 daltons, and mixtures thereof,hydrogenated vegetable oils, glycerinated gelatin or mixtures thereof.

The matrix composition may in addition include a cellulose derivative,e.g. a cellulose derivative selected from the group consisting ofmethylcellulose, carboxymethylcellulose and salts thereof,microcrystalline cellulose, ethylhydroxyethylcellulose,ethylmethylcellulose, hydroxyethylcellulose,hydroxyethylmethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, hydroxymethylcellulose andhydroxymethylpropylcellulose. Of these cellulose derivatives,hydroxypropylmethylcellulose and methylcellulose are preferred forincorporation in the matrix composition.

Furthermore, the matrix composition may comprise one or more agentsselected from the group consisting of sweetening agents, flavouringagents and colouring agents, in order to provide an elegant andpalatable preparation. Examples of colouring agents are water solubleFD&C dyes and mixtures thereof with corresponding lakes and directcompression sugars such as Di-Pac from Amstar. In addition, coloured dyemigration inhibitors such as tragacanth, acacia or attapulgite talc maybe added. Specific examples include Calcium carbonate,Chromium-cobalt-aluminium oxide, ferric ferrocyanide, Ferric oxide, Ironammonium citrate, Iron (III) oxide hydrated, Iron oxides, Magnesiumcarbonate, Titanium dioxide.

Examples of suitable fillers are also dextrin, sucralfate, calciumhydroxyl-apatite, calcium phosphates and fatty acid salts such asmagnesium stearate.

The filler may be added in an amount so that the combination of thefiller and the active substance comprises up to about 60%, typically upto about 50%, by weight of the first composition.

In order to soften the carrier system, a plasticziser may beincorporated in the composition. A suitable plasticizer is selected fromthe group consisting of phosphate esters; phthalate esters; amides;mineral oils; fatty acids and esters; fatty alcohols, vegetable oils andhydrogenated vegetable oils including acetylated hydrogenated cottonseedglyceride and acetylated hydrogenated soybean oil glycerides; acetyltributyl citrate, acetyl triethyl citrate, Castor oil, diacetylatedmonoglycerides, dipropylene glycol salicylate glycerin, glycerylcocoate, mono- and di-acetylated monoglycerides, nitrobenzene, carbondisulfide. β-naphtyl salicytate, phthalyl glycolate, diocyl phthalate;sorbitol, sorbitol glyceryl tricitrate; sucrose octaacetate;a-tocopheryl polyethylene glycol succinate, phosphate esters; phthalateesters; amides; mineral oils; fatty acids and esters; fatty alcohols;and vegetable oils, fatty alcohols including cetostearyl alcohol, cetylalcohol, stearyl alcohol, oleyl alcohol and myristyl alcohol; methylabietate, acetyl tributyl citrate, acetyl triethyl citrate, diisooctyladipate, amyl oleate, butyl ricinoleate, benzyl benzoate, butyl andglycol esters of fatty acids, butyl diglycol carbonate, butyl oleate,butyl stearate, di(beta-methoxyethyl) adipate, dibutyl sebacate, dibutyltartrate, dilsobutyl adipate, dihexyl adipate, triethylene glycoldi(beta-ethyl butyrate), polyethylene glycol di(2-ethyl hexoate),diethylene glycol monolaurate, monomeric polyethylene ester,hydrogenated methyl ester of rosin, methoxyethyl oleate, butoxyethylstearate, butyl phthalyl butyl glycolate, glycerol tributyrate,triethylene glycol dipelargonate, beta-(p-tert-amyl phenoxy)ethanol,beta(p-tert-butytphenoxy)ethanol,beta-(p-teft-butytphenoxyethyl)acetate,bis(beta-p-tert-buthylphenoxydiethyl)ether, camphor, Cumar W-1, CumarMH-1, Cumar V-1, diamyl phthalate, (diamylphenoxy) ethanol, diphenyloxide, technical hydroabietyl alcohol, beckolin, benzenehexahydrochlonde,Clorafin 40, Piccolastic A-5, Piccalastic A-25, FlexolB-400, Glycerol alfa-methyl alfa-phenyl ether, chlorinated naphthalene,HB-40, monoamylphthalate. Nevillac 10 o-nitrodiphenyl and Paracril 26.

Preferred anti-oxidative agents include TPGS due to surfactantproperties, BHA, BHT, t-butyl hydroquinone, calcium ascorbate, gallicacid, hydroquinone, maltol, octyl gallate, sodium bisulfite, sodiummetabisulfite,tocopherol and derivates thereof, citric acid, tartaricacid, and ascorbic acid. Other antioxidants include trivalentphosphorous like e.g phosphite, phenolic antioxidants, hydroxylamines,lactones such as substituted benzofuranones. Hindered phenols,thiosynergists and/or hindered amines are useful for the long-termstability for polymers, whereas the following antioxidants are suitablefor use also in situation where the active substance is subject tooxidation: acids (ascorbic acid, erythorbic acid, etidronic acid, gallicacid, hypopphsphorous acid, nordihydroguairetic acid, proplonic acidetc.), phenols (e.g. BHA, BHT, t-butyl hydroquinone, dodecyl gallate,octyl gallate, 1,3,5-trihydroxybenzene), organic and inorganic salts(calcium ascorbate, sodium ascorbate, sodium bisulphite, sodiummetabisulfite, sodium sulfite, potassium bisulphite, potassiummetabisulphite), esteres (calcium ascorbate, dilauryl thiodipropionate,dimyristyl thiodiproplonate, distearyl thiodipropionate), pyranon(maltol), and vitamin E (tocopherol, D-α-tocopherol, DL-α-tocopherol,tocopheryl acetate, d-α-tocopheryl acetate, dl-α-tocopheryl acetate.However, other anti-oxidative agents known in the art may be usedaccording to the present invention.

pH Dependant Release

In some situations it may be convenient that the composition releasesthe active substance in a pH dependant manner. As described in e.g. WO99/51208 a pH dependant release can be obtained by inclusion of aso-called release rate modifier. The release rate modifier is preferablyselected from materials conventionally used in the pharmaceuticalindustry to produce enteric coatings. A number of different types ofcompounds suitable for use as enteric coatings are known in the art; seee.g. Remington's Pharmaceutical Sciences, 18^(th) Edition, 1990. Releasemodifiers may in particular be selected from one of three generalclasses, namely cellulose derivatives, methacrylic acid polymers andmodified gelatine compounds. Preferred release modifiers includecellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and hydroxypropyl methylcellulose acetatesuccinate, as well as methacrylic acid copolymers. Modified gelatinecompounds include gelatine treated with e.g. formaldehyde orglutaraldehyde.

Examples of commercially available polymers suitable as releasemodifiers are EUDRAGIT® L and EUDRAGIT® S, available from Röhm GmbH,Germany, and enteric coating agents available from Shin-Etsu ChemicalCo., Japan. The release modifier will typically be present in thecomposition in an amount of about 0.1-10%, based on the weight of thematrix, preferably about 0.5-4%, e.g. about 1-3%, such as about1.5-2.0%. If desired, a suitable mixture of more than one releasemodifier may be used in order to obtain a desired release profile in anygiven composition.

The release modifier enables a difference in release of the activesubstancelerosion of the matrix dependant on pH.

Shape

The geometric form of the composition is important for the obtainment ofthe above-mentioned controlled zero order. Thus, in a preferred versionof the invention, the pharmaceutical composition of the invention has ageometric shape, which enables a substantially constant surface area tobecome exposed during erosion of the matrix.

In order to achieve a higher plasma concentration 5-10 hours afteradministration it is contemplated that a shape is suitable that exposesan increasing surface area during the first 1-3 hours and then exposes aconstant surface area. Examples of such shapes are given in FIG. 1B.

Specific examples of compositions with different shapes and sizes are:

Batch Length [mm] Diameter [mm] Vol [mm³] 01-0034-042 7.5 5.05 15001-0035-042 6.0 5.64 150 01-0043-042 9.0 4.6 150

The following table describes formulations having a cylindrical form andoval openings in both ends

Longest/shortest Batch Length [mm] Vol [mm³] diameter [mm] 01-0075-0426.0 150 8.74 3.64 01-0076-042 7.5 150 7.82 3.21

The coated compositions obtained were open at two opposite ends.

The area for an open end is calculates as the volume/length of thecylindrical formulations

Coating

The pharmaceutical composition may thus have the shape of a cylindricalrod, which is provided with a coating, which is substantially insolublein and impermeable to fluids such as body fluids during the intendedrelease period, the coating having an opening at one or both ends.Polymers useful as coatings are preferably those, which are possible toprocess by extrusion, solution or in the form of a dispersion. Mostpreferred are those, which are available in a food grade or apharmaceutical grade quality. Examples of such polymers are celluloseacetate, polyamide, polyethylene, polyethylene terephthalate,polypropylenem polyurethane, polyvinyl acetate, polyvinyl chloride,silicone rubber, latex, polyhydroxybutyrate, polyhydroxyvalerate,teflon, polylactic acid or polyglycolic acid and copolymers thereof,copolymers such as ethylene vinyl acetate (EVA),styrene-butadienestyrene (SBS) and styrene-isoprene-styrene (SIS).

The coating may also be a coating, which is substantially soluble in andpermeable to fluids such as body fluids during the intended releaseperiod provided that the coating dissolves so much slower than thematrix composition that the coating remains intact until the matrix haseroded and released the active substance. Examples of suitable polymersinclude polyols as described herein.

The coating may further comprise any of the above-mentioned matrixmaterials in a form, which erodes at a substantially slower rate thanthe rest of the matrix. The coating may thus comprise a matrix of one ormore substantially water soluble crystalline polymers and, optionally, anon-ionic emulsifier, the coating being one which is eroded in theaqueous phase at a substantially slower rate than the matrix compositioncomprising the active substance, whereby a substantially constant areaof the matrix composition comprising the active substance is exposedduring erosion of the matrix composition, and whereby the coating issubstantially eroded upon erosion of the matrix composition comprisingthe active substance. Such a coating will be designed so that itslongitudinal erosion rate is substantially the same as the longitudinalerosion rate of the matrix, whereby the matrix and the coating willerode longitudinally towards the centre of the composition atsubstantially the same rate. Thus, when the matrix composition has beencompletely eroded by the aqueous medium, the coating will also besubstantially completely eroded. A matrix composition having such acoating has the obvious advantage of being completely biodegraded uponrelease of the active substance. Such a coating will typically be acombination of a polyethylene glycol and a mixture of, for example,polyethylene glycol 400 monostearate or another non-ionic emulsifier,and may also include a filler. The content of the mixture of non-ionicemulsifiers and the filler in the coating will be determined in eachparticular case according to the characteristics, e.g. erosion rate andsize, of the matrix comprising the active substance.

In an embodiment of the invention, the coating is one, whichdisintegrates or crumbles after erosion of the matrix. A coating of thistype will remain intact as long as it is supported by the matrixcontaining the active substance, but it lacks the ability to remainintact after erosion of the matrix, because it then disintegrates orcrumbles, so that it will not remain in e.g. a human or animal for anysignificant amount of time after the complete erosion of the matrix andthe release of the active substance.

The coating may also be an enteric coating employing methacrylates, aco-polymer of methacrylate-galactomannan etc.

In an interesting embodiment, the controlled release composition of theinvention further comprises a coating having at least one openingexposing at least one surface of the matrix, the coating being one whichcrumbles and/or erodes upon exposure to the aqueous medium at a ratewhich is equal to or slower than the rate at which the matrix erodes inthe aqueous medium, allowing exposure of said surface of the matrix tothe aqueous medium to be controlled. Coatings of this type are describedin WO 95/22962, to which reference is made and which is incorporatedherein by reference. These coatings comprise:

-   -   (a) a first cellulose derivative which has thermoplastic        properties and which is substantially insoluble in the aqueous        medium in which the composition is to be used, e.g. an        ethylcellulose such as ethylcellulose having an ethoxyl content        in the range of 44.5-52.5%, or cellulose acetate, cellulose        propionate or cellulose nitrate;        and at least one of:    -   (b) a second cellulose derivative which is soluble or        dispersible in water, e.g. a cellulose derivative selected from        the group consisting of methylcellulose, carboxymethylcellulose        and salts thereof, cellulose acetate phthalate, microcrystalline        cellulose, ethylhydroxyethylcellulose, ethylmethylcellulose,        hydroxyethylcellulose, hydroxyethylmethylcellulose,        hydroxypropylcellulose, hydroxypropylmethylcellulose,        hydroxymethylcellulose and hydroxymethylpropyfcollulose;    -   (c) a plasticizer, e.g. selected from the group consisting of        phosphate esters; phthalate esters; amides; mineral oils; fatty        acids and esters thereof with polyethylene glycol, glycerin or        sugars; fatty alcohols and ethers thereof with polyethylene        glycol, glycerin or sugars; and vegetable oils; or a non-ionic        surfactant; and    -   (d) a filler, e.g. selected from conventional tablet or capsule        excipients such as diluents, binders, lubricants and        disintegrants.

The use of a plasticizer will often be desirable inorder to improve theprocessability of the ethylcellulose or the first cellulose derivative.The plasticizer may also be a non-ionic surfactant, e.g. a non-ionicsurfactant selected from the group consisting of diacetylatedmonoglycerides, diethylene glycol monostearate, ethylene glycolmonostearate, glyceryl monooleate, glyceryl monostearate, propyleneglycol monostearate, macrogol esters, macrogol stearate 400, macrogolstearate 2000, polyoxyethylene 50 stearate, macrogol ethers,cetomacrogol 1000, lauromacrogols, nonoxinols, octocinols, tyloxapol,poloxamers, polyvinyl alcohols, polysorbate 20, polysorbate 40,polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, sorbitanmonolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitanmonostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitantristearate and sucrose esters; nitrobenzene, carbon disulfide,β-naphtyl salicylate, phthalyl glycolate, dioctyl phthalate.

Other suitable plasticizers appear from EP-B-0 746 310 to whichreference is made.

Pharmaceutical Composition

As mentioned above a pharmaceutical composition according to theinvention is a coated matrix composition from which the active substanceis released by a zero order release mechanism.

A composition according to the invention containing a drug substance istypically for oral administration and may be in the form of a tablet ora capsule or in the form of a multiple unit dosage form. Due to thepossibility of controlling the release rate of the active substance thecomposition may be adapted for oral administration 1-6 times a day,normally 1-4 times daily such as 1-3 times, 1-2 times or 1 times daily.The technology may also provide compositions for administration onlyonce or twice daily. In the present context the term “once daily” isintended to mean that it is only necessary to administer thepharmaceutical composition once a day in order to obtain a suitabletherapeutic and/or prophylactic response; however, any administrationmay comprise co-administration of more than one dosage unit, such as,e.g. 2-4 dosage units if the amount of active substance required may notbe formulated in only one composition or if a composition of a smallersize is preferred.

The dosage of the active substance depends on the particular substance,the age, weight condition etc. of the human or animal that will betreated with the composition etc. All such factors are well known to aperson skilled in the art.

The controlled release of the active substance is caused by erosion at asubstantially constant rate of a surface or surfaces of the composition

The rate at which the active substance is released from the matrix is apredetermined rate, i.e. a rate, which is controllable over a certainperiod of time. The release rate required in each particular instancemay inter alia depend on the amount of active substance to be releasedfor it to exert the desired effect, as well as on the overall dosage ofthe active substance contained in the matrix. The substance of which thematrix is composed and the distribution of the active substance in thematrix may therefore be selected according to one or more of thesecriteria to ensure the desired level of release of the active substance.

Due to the controlled release of the active substance obtainable fromthe pharmaceutical composition of the invention, it is possible toobtain a substantially constant rate of release of the active substanceover a specific period of time, corresponding to the dosage necessaryfor the treatment in question, so that adherence to a strict dosageregimen, e.g. requiring administration of a drug at set intervals up toseveral times a day, may be dispensed with.

Furthermore, it is possible to include two or more different activesubstances in the pharmaceutical composition of the Invention, and thetwo or more different active substances may be adapted to be released atdifferent concentrations and/or intervals, thus making it easier forpatients to follow a prescribed regimen.

An additional advantage of a pharmaceutical composition of theinvention, compared to other known controlled release compositions, isthat it may be produced by relatively simple and inexpensive methods.

Furthermore, a pharmaceutical composition according to the inventionallows for the incorporation of high concentrations of the activesubstance relative to the size of the delivery system. This is obviouslya great advantage, notably when the composition is to be used for thedelivery of a therapeutically, prophylactically and/or diagnosticallyactive substance, since it allows for the delivery of the requiredamount of the active substance without the size of the composition beingunnecessarily large. In addition, sparingly soluble or non-solubleactive substances may be readily incorporated into a composition of theinvention. A composition of the invention may thus be used for thedelivery of, for example, sparingly soluble or non-solublepharmaceutical powders which can otherwise be difficult to administer.

As mentioned above, the release of the active substance from thepharmaceutical composition corresponds to a substantially zero orderrelease determined by in vitro dissolution test according to USP. Thesubstantially zero order release is obtained in a time period of atleast 1 hours such as, e.g. at least 2 hours, at least 3 hours, at least4 hours or at least 5 hours, or in a time period of at least 5 hourssuch as, e.g. at least 6 hours, at least 7 hours, at least 8 hours, atleast 9 hours or at least 10 hours.

Opiod Compositions

In the experimental section herein examples are given on suitablemorphine containing compositions, which are based on the conceptdescribed herein.

In an embodiment the invention relates to

a pharmaceutical composition for controlled release of an opioid or apharmaceutically acceptable salt or metabolite thereof into an aqueousmedium by erosion of at least one surface of the composition, thecomposition comprising

i) a matrix composition comprising a) polymer or a mixture of polymers,b) an opioid and, optionally, c) one or more pharmaceutically acceptableexcipients, and

ii) a coating having at least one opening exposing at the one surface ofsaid matrix, the coating comprising

-   -   a) a first cellulose derivative which has thermoplastic        properties and which is substantially insoluble in the aqueous        medium in which the composition is to be used,        and at least one of    -   b) a second cellulose derivative which is soluble or dispersible        in water,    -   c) a plasticizer, and    -   d) a filler,        and the concentration and/or the nature of the ingredients        making up the matrix composition has been adjusted in such a        manner that the diffusion rate of the aqueous medium into the        matrix composition corresponds to about 100%±30% such as, e.g.        about 100%±25%, about 100% 20%, about 100%±15% or about 100%±10%        or about 100% of the dissolution rate of the matrix composition        so as to obtain a zero order release of at least about 60% w/w        such as, e.g. at least about 65% w/w at least about 70% w/w, at        least about 75% w/w, at least about 80% w/w, at least about 85%        w/w, at least about 90% w/w, at least about 95% w/w or at least        about 97 or 98% w/w of the active substance from the        pharmaceutical composition when subject to an in vitro        dissolution test as described herein.

Especially suitable polymers are those of the polyol type describedherein such as, e.g. polyethylene glycol, a polyethylene oxide and/or ablock copolymer of ethylene oxide and propylene oxide. The polymers havea molecular weight of from about 20,000 daltons, such as, e.g., fromabout 20.000 to about 700,000 daltons, from about 20,000 to about600,000 daltons, from about 35,000 to about 500,000 daltons, from about35,000 to about 400,000 daltons, from about 35,000 to about 300,000daltons, from about 50,000 to about 300,000 daltons, such as, e.g. about35,000 daltons, about 50,000 daltons, about 75,000 daltons, about100,000 daltons, about 150,000 daltons, about 200,000 daltons, about250,000 daltons, about 300,000 daltons or about 400,000 daltons.

From the examples it is seem that employment of PEO 200,000 leads to asuitable composition.

Suitable pharmaceutically acceptable excipients are also describedherein such as, e.g. inorganic acids, inorganic bases, inorganic salts,organic acids or bases and pharmaceutically acceptable salts thereof,saccharides, oligosaccharides, polysaccharides, and cellulose andcellulose derivatives. The organic acid may be a mono-, di-, oligo orpolycarboxylic acid such as, e.g. acetic acid, succinic acid, citricacid, tartaric acid, acrylic acid, benzoic acid, malic acid, maleic acidetc.

From the examples it is seem that employment of mannitol or a base likealuminium oxide leads to a suitable composition.

Accordingly, in a specific embodiment the invention relates to apharmaceutical composition in which the matrix composition comprisesmorphine, PEO 200,000 and mannitol and/or aluminium oxide.

Multiple Units Composition

The pharmaceutical composition according to the invention mayfurthermore be used in the preparation of a multiple unitspharmaceutical composition, e.g. in the form of a capsule or tablet. Amultiple units pharmaceutical composition is a composition, whichcomprises a multiplicity of individual units in such a form that theindividual units will be made available upon disintegration of thecomposition, typically a capsule or tablet, in the stomach of humans oranimals ingesting said composition. Thus, in this case, at least some ofthe individual units in said multiple units pharmaceutical compositionwill consist of the composition of the invention, the individual unitsbeing of a size, which allows them to be incorporated into such acomposition.

Preparation

The delivery system as well as the first composition of the inventionmay be produced by various methods which are either known per se in thepharmaceutical industry or which, for example, are used in theproduction of polymer-based materials, depending upon the desiredembodiment and the materials employed in the composition in question. Asmentioned above, one advantage of the composition according to theinvention is that it may be produced by methods, which are relativelysimple and inexpensive.

A pharmaceutical composition may be produced by, for example,co-extrusion of the coating with the matrix composition and the activesubstance, extrusion and dip coating, injection moulding and dipcoating, or by extrusion or injection moulding and solvent coating byspraying or dipping.

For further details reference is made to the experimental sectionherein.

Method for Controlling the Release

As mentioned above, the invention also relates to a method forcontrolling the release of a therapeutically, prophylactically and/ordiagnostically active substance from a pharmaceutical composition. Tothis end all details and particulars described above under thecomposition aspect applies mutatis mutandi to the method aspect and toother aspects of the invention.

The invention is further illustrated in the following figures andnon-limiting examples.

FIG. 1A is a plug holder suitable for use when determining diffusion anddissolution rate. A stopper on the right seals the plug holder, and theswelling layer is formed on the left side on the plug.

FIG. 1B is a suitable shape for an opioid composition. Suitable valuesare e.g. a=3 mm, b=4.5 mm, c=1.5 mm and d=9 mm; a=3 mm, b=4.6 mm, c=2 mmand d=9 mm; a=2.3 mm, b=5.3 mm, c=1.5 mm and d=7.5 mm; or a=3.4 mm,b=5.1 mm, c=2 mm and d=7.5 mm

FIG. 2 is the dissolution profile from the composition of Example 1.

FIGS. 3 (1A, 16, 2A and 2B) shows the dissolution profiles from thecompositions of Example 2.

FIG. 4 shows the plasma concentration vs. time profile for the clinicalstudy on healthy volunteers reported in Example 3.

FIG. 5 shows the plasma concentration vs. time profile for the clinicalstudy in phase II reported in Example 3.

METHODS

Diffusion/Dissolution Studies

Method for Determination of Dissolution Rate of the Matrix

A composition according to the invention has properties that ensure thatthe diffusion rate of water into the polymer matrix substantiallycorresponds to the dissolution rate of the polymer matrix compositioninto the aqueous medium. In the following is given a simple method totest these conditions.

The polymers that are suitable for use according to the presentinvention and which are sufficiently hydrophilic are water-soluble. Whencontacted with water, a sharp advancing waterfront divides the intactand not penetrated matrix from a swollen front. Under stationaryconditions, a constant thickness surface layer is formed by the swollenpolymer and by a high concentration of polymer in solution.

In fact, once the hydrodynamic external conditions are defined, astationary state is reached where the rate of penetration of the movingboundary equals the rate of removal of the polymer at the externalsurface.

The time lapse until the quasi-stationary state is reached is calledswelling time. At steady state, the dissolution rate is constant and canbe defined equally by either the velocity of the retracting front of thepolymer or the velocity of the front separating the pure penetrate andthe liquid dissolving sublayer. Thus, both fronts are synchronized.

When the dissolution rate equals the penetration rate (i.e. thediffusion rate) a constant thickness surface layer should be observed.The dissolving layer evolution during water conditioning should reflectthe different dissolution characteristics of the materials employed. Thesurface layer thickness is measured as a function of time.

In order to measure the diffusion rates of water, samples may beprepared in the form of plugs fitting to the sample holder (e.g. 2 mm, 4mm, 6 mm, 7.5 mm and 12 mm long and preferable with the same shape andvolume as the desired dosage unit). The sample holder is prepared bytranslucent glass in a tubular shape and with noticeable marks indicatedwith a specific distance.

The test proceeds as follows: Place 1 plug incorporated into the glasstube in a vessel—optionally with a water soluble dye (e.g. Cu²⁺)—and theplug/glass tube is placed in a dissolution apparatus e.g. according tomonograph: USP 24, page 1941-1950, which is hereby incorporated byreference (see FIG. 1A). By employment of the USP method it is possibleto determine the diffusion rate as well as the dissolution rate in thesame experiment. The copper ions are blue-coloured so they are visuallydetectable and due to the metric scale on the tube, the diffusion ratecan be calculated (unit is length/time). The dissolution rate isdetermined by determining the amount of substance (e.g. activesubstance) released and at the same time determining the length of thematrix composition that has been eroded. Thus, the dissolution rate isalso in length/time units. As the dissolution profile easily can beobtained from the data measured, a simple means for the determination ofwhether the release follows zero order is to investigate the dissolutionprofile and see whether linearity is present.

Agitation is provided, and the length of the front of matrix is measuredat desired time intervals as a function of time. The measurement may bea simple visual identification of the marks on the glass tube.

When the dissolution rate equals the penetration rate a constantthickness surface layer is observed. The different dissolving layers indifferent matrices obtained during the water contact, reflect thedifferent dissolution characteristics of the matrix. The thickness ofthe surface layer as a function of time is then compared. The specificaqueous medium may be selected individually.

Dissolution Test

Dissolution tests were performed in accordance with the USP 24, NF 19,(711) Dissolution, Apparatus 2 equipped with a paddle. The dissolutionmedium was 0.1 N hydrochloric acid during the first 120 min, which wasthen substituted with a buffer solution pH 6.8. The volume of thedissolution medium was 1000 ml and the rotation speed of the paddle was120 rpm during the first 120 min and then 50 rpm. Samples were withdrawnat suitable time intervals and analyzed for content of opioid by meansof UV spectrometry at a wavelength of 284 nm.

EXAMPLES

A general method for the preparation of a controlled release compositionis described below.

Preparation of the Matrix Composition

An accurate amount of the polymer (i.e. in the examples below: thepolyethylene oxide) is loaded into a MTI mixer followed by an accurateamount of the active substance and of the pharmaceutically acceptableexcipients(s), if any. The mixing is performed at 2000/1500 rpm and at atime period of from 10 min to 20 min. At the start of the mixing thetemperature is about 19° C. and the final temperature of the mixture isabout 40-43° C. The mixture is then allowed to cool to room temperatureand is ready to be fed into an injection moulding machine.

When TPGS is included in the composition, TPGS and PEO are premixed byadding melted TPGS to PEO followed by mixing.

Preparation of the Coating Composition

The coating composition was prepared by first adding thehydroxymethylcellulose then cetostearyl alcohol, and finally thetitanium dioxide to an MTI-Mixer at a temperature about 21° C. Aftermixing for nearly 9 min at 1000 rpm (I: 0.9 A) the mixer was stopped(temperature about 46° C.) and the adhered material manuallyincorporated into the mixture. The mixture was left to cool for about 10minutes. The mixing is then finalized with a short high-speed mix inorder to minimize lumps formation. The mixture was then allowed to coolto room temperature, after which it had a suitable consistency for beingfed into an injection moulding machine.

Example of Coat Composition

-   -   Batch: 58-014-01-013

amount Weight % Batch Material (g) (g) step 79 991207-A Ethocel 632 6321 20 990426-B Cetylstearyl Alkohol 160 160.1 2 1 97051301 TiO₂ 8 8.0 3100 total 800 800.1

The final dosage units may be prepared according to two differentmethods.

In one method, the coat and the matrix moulded individually followed bya manually incorporation of the moulded matrix plug into the mouldedcoat. The moulding machine used is an Arburg Allrounder 220 S 250/60.

In the second method, the coat and matrix are moulded in one processwhere the coat is moulded in a first step and the matrix is mouldeddirectly into the coat in a second step. The moulding machine used isArburg Allrounder 420 V 800-60/35.

EXAMPLES Example 1 Preparation of a Morphine Containing ControlledRelease Composition According to the Invention

A composition (batch No. 01-0112-066) according to the invention wasprepared from the following ingredients:

Matrix Polyethylene oxide 200,000 83.5% w//w Morphine sulfate 16.5% w/w

The coating and the matrix were prepared as described above. Thecomposition was 9 mm long and had elliptic formed surfaces.

The composition was subjected to the dissolution test described above.The following results were obtained:

Time (hours) % w/w release morphine sulfate from the composition 1 19.482 33.64 3 44.22 4 55.59 5 70.11 6 80.70 7 91.30 8 96.65

The result is also shown in FIG. 2 and the release corresponds to a zeroorder release.

Example 2 Preparation of Morphine-Containing Compositions According tothe Invention

In the table below is given details on the composition of 4 differentmorphine compositions. The content of morphine sulphate in allcompositions corresponds to 30 mg morphine sulphate. The volumes of thedifferent compositions were the same, whereas 10 the diameter of theopen end surfaces varies.

Composition (% w/w) PEO Morphine AlO₂, No. Length/mm 200.000 SulphateTPGS 3H2O Mannitol 1B 7.5; Ellipse^(a) 76.5 18.7 2.5 2.3 2B 12;round^(b) 68.7 18.7 2.6 10.0 2A 9; round^(c) 69.9 17.5 2.6 10.0 1A 9;round^(d) 77.3 17.9 2.5 2.4 ^(a)150 mm³/20 mm² ^(b)137 mm³/diameter 5 mm^(c)150 mm³/16.67 mm² ^(d)150 mm³/16.67 mm²

All compositions demonstrated 6 months accelerated stability at 40°C./75% RH and 12 months stability at 25° Cn5% RH. In all compositionseach single impurity is below 0.1% 20 w/w.

In the following is given the data for the dissolution profiles of eachcomposition:

Composition 2A (see FIG. 3-2A):

% active Substance Time/h dissolved 0.0 −0.36 1.0 23.45 20.0 2.0 41.335.2 3.0 59.5 50.7 4.0 75.93 64.7 5.0 90.83 77.4 6.0 107.34 91.5 6.5113.26 96.6 7.0 116.67 99.4 7.5 117.24 100 8.0 117.28 100

Composition 2B (see FIG. 3-2B)

% active Substance Time/h dissolved 0.0 −0.48 1.0 19.22 16.9 2.0 34.4430.0 3.0 44.3 39.0 4.0 55.52 48.8 5.0 66.13 58.2 6.0 76.93 67.7 7.087.19 76.7 8.0 98.11 86.3 9.0 109.04 96.0 9.5 111.26 97.8 10.0 112.6399.1 10.5 113.48 100 11.0 113.66 100

Composition 1B (see FIG. 3-1B)

% active substance Time/h dissolved 0.0 −0.47 1.0 30.15 23.7 2.0 55.7243.9 3.0 77.54 61.1 4.0 97.55 76.8 5.0 117.57 92.6 5.5 124.77 98.2 6.0126.89 100 6.5 126.93 100

Composition 1A (see FIG. 3-1A)

% active Substance Time/h dissolved 0.0 −0.423 1.0 23.17 19.3 2.0 40.4733.8 3.0 53.27 44.4 4.0 67.13 56.0 5.0 80.67 67.3 6.0 101.23 84.4 7.0108.16 90.2 7.5 114.53 95.6 8.0 119.78 100

The results show that the use of mannitol or aluminiumoxide as a DDAleads to the desired zero order release of morphine sulphate from acomposition according to the 5 invention. The above-mentionedcompositions were subject to a clinical study. The clinical study isreported in the following example.

Example 3 A Single Dose, Randomized, Cross-Over, Pharmacokinetic PilotStudy on Four Different Morphine Compositions According to the Invention

The objectives were to study the pharmacokinetics of morphine afteradministration of four different morphine compositions according to theinvention. The compositions had different shape and size and the DDAsemployed in order to enable a zero order dissolution profile weredifferent (mannitol and aluminium oxide, respectively).

16 healthy male volunteers aged 20 to 40 who had given their writteninformed consent were included in the study.

The volunteers were screened up to three weeks prior to baseline. Thefirst treatment was administered at the baseline visit and secondtreatment was administered after 2 weeks of wash out. Follow-up visitstook place 30 days after the second study period.

The compositions tested were those described in Example 2 above. Thedose given corresponds to 30 mg morphine sulphate.

-   -   The results of the study are shown in FIG. 4. In FIG. 4 is also        included data for a comparative composition, Dolcontin. The        results indicate that the shape as well as the size of the        composition are important.        -   Another clinical study has also been performed as a phase            II, open, prospective, controlled study in patients with            chronic pain. The study included 13 patients with chronic            pain for any reason judged by the investigator as stable and            in need of oplolds analgesics. A composition according to            the Invention was tested and compared with a commercially            available morphine containing composition, Dolcontin. The            total morphine sulphate released from the composition            according to the Invention was about 20 mg (the dosage in            Dolcontin was 30 mg). Although there was a difference in the            amount administered, it was evident from the study that the            therapeutic effect of a composition according to the            invention was not different from Dolcontin, i.e. a reduction            is the overall dose may be reduced by the use a zero order            release composition. Moreover, the adverse effects reported            were less compared to the Dolcontin composition, most likely            due to the smaller amount of morphine sulphate administered.            Another interesting feature is that during the study rescue            medication was allowed and there was no difference in the            Intake of rescue medicine of patients administered with            Dolcontin or with a composition according to the invention.            FIG. 5 shows the plasma concentration versus time profiles            from the study.

The invention claimed is:
 1. A controlled release pharmaceuticalformulation for oral delivery of hydrocodone or oxycodone consisting ofa single injection molded matrix having a coating, wherein: the singleinjection molded matrix has a cylindrical shape and comprises atherapeutically effective amount of hydrocodone or oxycodone or apharmaceutically acceptable salt thereof and one or more polyethyleneoxides, wherein the average molecular weight of the one or morepolyethylene oxides present in the matrix is from about 200,000 to about300,000 daltons; and the coating on the matrix has at least one openingexposing an end surface of the matrix to permit release of thehydrocodone or oxycodone from the matrix by erosion of the matrix, andis insoluble and impermeable to body fluids during the intendedhydrocodone or oxycodone release period; wherein the coating and thematrix are formed by injection molding, wherein the formulation exhibitszero order release of at least 60% of the hydrocodone or oxycodone fromthe formulation when subject to an in vitro dissolution test accordingto USP 24, NF 19, 711 Dissolution, employing Apparatus 2 equipped with apaddle using 1000 mL of 0.1 N hydrochloric acid dissolution medium and apaddle rotation of 120 rpm for the first 120 minutes, and a buffersolution having a pH of 6.8 and a paddle rotation of 50 rpm thereafter.2. The pharmaceutical formulation of claim 1, wherein the one or morepolyethylene oxides comprise at least two polyethylene oxides.
 3. Thepharmaceutical formulation of claim 1, wherein at least one polyethyleneoxide has a molecular weight of about 200,000 or about 300,000 daltons.4. The pharmaceutical formulation of claim 1, wherein the matrix furthercomprises a plasticizer.
 5. The pharmaceutical formulation of claim 1,wherein the matrix further comprises a block copolymer of ethylene oxideand propylene oxide.
 6. The pharmaceutical formulation of claim 1,wherein the matrix further comprises a block copolymer of ethylene oxideand propylene oxide having a molecular weight of from about 5,000 toabout 30,000 daltons.
 7. The pharmaceutical formulation of claim 1,wherein the matrix further comprises a poloxamer.
 8. The pharmaceuticalformulation of claim 1, wherein the matrix further comprises anantioxidant.
 9. The pharmaceutical formulation of claim 8 wherein theantioxidant is butylhydroxytoluene.
 10. The pharmaceutical formulationof claim 1, wherein the matrix further compriseshydroxypropylmethylcellulose.
 11. The pharmaceutical formulation ofclaim 1, wherein the coating remains intact during release of thehydrocodone or oxycodone from the formulation following oraladministration to a human.
 12. The pharmaceutical formulation of claim1, wherein the coating comprises a plasticizer.
 13. The pharmaceuticalformulation of claim 1, wherein the coating comprises one or morepolylactic acid polymers.
 14. The pharmaceutical formulation of claim 1,wherein the coating comprises a material selected from the groupconsisting of cellulose acetate, polyamide, polyethylene, polyethyleneterephthalate, polypropylene, polyurethane, polyvinyl acetate, polyvinylchloride, silicone rubber, latex, polyhydroxybutyrate,polyhydroxyvalerate, teflon, polylactic acid or polyglycolic acid andcopolymers thereof, ethylene vinyl acetate (EVA),styrene-butadienestyrene (SBS), and styrene-isoprene-styrene (SIS). 15.The pharmaceutical formulation of claim 1, wherein the formulation issuitable for once-daily oral dosing.
 16. The pharmaceutical formulationof claim 1, wherein the formulation is suitable for twice-daily oraldosing.
 17. The pharmaceutical formulation of claim 1, wherein theformulation is prepared by injection molding the matrix inside thecoating.
 18. The pharmaceutical formulation of claim 1, wherein thecoating and the matrix are each prepared by separate injection moldingprocesses.
 19. The pharmaceutical formulation of claim 1, wherein atleast one end of the matrix is tapered and wherein at least one openingof the coating exposes the tapered end, to expose an increasing surfacearea during the first 1-3 hours of matrix erosion following oraladministration to a human.
 20. The pharmaceutical formulation of claim1, wherein the matrix further comprises one or more methacrylic acidcopolymers.